This invention relates to 1,2,3-substituted indoles which are useful as lipoxygenase inhibitors. More specifically, this invention relates to indoles wherein the nitrogen is substituted by an alkyl or benzyl group, the 2-position is substituted by the group --Y--(CH.sub.2).sub.n NH.sub.2, and position 3 has an --S(O).sub.m aryl group.
These compounds are useful for treating inflammation as they are inhibitors of human polymorphonuclear leukocyte lipoxygenase. This lipoxygenase catalyzes the hydroperoxidation of polyunsaturated fatty acids, esters, alcohols, etc., containing a cis-cis-1,4-pentadiene system. The product is a 1-hydroperoxy-2,4-trans,cispentadiene-containing molecule.
Of particular interest is the conversion of arachidonic acid to leukotrienes. Leukotrienes, eariler known as slow reacting substance of anaphylaxis, are known to be involved in inflammation and anaphylaxis. The compounds of this invention are useful for treating inflammation, asthma, diverse allergic states, adult respiratory distress syndrome, psoriasis, gout, etc., as they inhibit the lipoxygenase enzyme responsible for conversion of arachidonic acid to leukotrienes from arachidonic acid by the lipoxygenase route. SUMMARY OF THE INVENTION
The novel compounds of this invention are those represented by formula I ##STR2## wherein R is alkyl of 1 to 8 carbon atoms, benzyl or benzyl substituted with one or more groups independently selected from the group alkyl of 1 to 4 carbon atoms, halo, --OR.sub.2 where R.sub.2 is alkyl of 1 to 4 carbon atoms, --OCF.sub.3, --SO.sub.2 CH.sub.3, --CO.sub.2 H, --CO.sub.2 R.sub.2, --CHO, --NO.sub.2, --CF.sub.3, --SCN, --OCH.sub.2 O--;
R.sub.1 is hydrogen or alkyl of 1 to 4 carbon atoms; PA1 Y is S, NH, or NR.sub.2 ; PA1 n is 2-8; PA1 m is 0,1 or 2; PA1 X and Z are independently alkyl of 1 to 4 carbon atoms, halo, --OR.sub.2 where R.sub.2 is alkyl of 1 to 4 carbon atoms, --OCF.sub.3, --SO.sub.2 CH.sub.3, --CO.sub.2 H, --CO.sub.2 R.sub.2, --CHO, --NO.sub.2, --CF.sub.3 or --SCN; PA1 p is 0, 1, 2, 3, 4, or 5; and the pharmaceutically acceptable salts thereof. PA1 R.sub.1 is hydrogen or alkyl of 1 to 4 carbon atoms; PA1 Y is S, NH, NR.sub.2, or; PA1 n is 2-8; PA1 m is 0,1 or 2; PA1 X and Z are independently alkyl of 1 to 4 carbon atoms, halo, --OR.sub.2 where R.sub.2 is alkyl of 1 to 4 carbon atoms, --OCF.sub.3, --SO.sub.2 CH.sub.3, --CO.sub.2 H, --CO.sub.2 R.sub.2, --CHO, --NO.sub.2, --CF.sub.3 or --SCN; PA1 p is 0, 1, 2, 3, 4, or 5; and the pharmaceutically acceptable salts thereof. DETAILED DESCRIPTION
In a second aspect, this invention relates to a method for treating inflammation which method comprises administering to a subject a therapeutically effective amount of a compound of formula I either alone or in admixture with a pharmaceutically acceptable excipient wherein formula I ##STR3## wherein R is alkyl of 1 to 8 carbon atoms, benzyl or benzyl substituted with one or more groups independently selected from the group alkyl of 1 to 4 carbon atoms, halo, --OR.sub.2 where R.sub.2 is alkyl of 1 to 4 carbon atoms, --OCF.sub.3, --SO.sub.2 CH.sub.3, --CO.sub.2 H, --CO.sub.2 R.sub.2, --CHO, --NO.sub.2, --CF.sub.3, --SCN, --OCH.sub.2 O;
The preferred compounds of this invention are those wherein Y is S. More preferred are those compounds wherein R is benzyl or substituted benzyl, Y is S, n is 2, m is 2, X is halo, alkyl of 1 to 4 carbon atoms; --OR.sub.2 or --COOR.sub.2, o is 1 and Z is hydrogen.
Most preferred are the compounds:
1-benzyl-2-aminoethylthio-3-phenylsulfonylindole; PA0 1-(2-methoxycarbonylbenzyl)-2-aminoethylthio-3-phenylsulfonylindole; PA0 1-(4-chlorobenzyl)-2-aminoethylthio-3-phenylsulfonylindole; PA0 1-(-4-methylbenzyl)-2-aminoethylthio-3-phenylsulfonylindole; PA0 1-benzyl-2-aminoethylthio-3-(4-methylphenylsulfonyl)indole; and PA0 1-benzyl-2-aminoethylthio-3-(4-chlorophenylsulfonyl)indole.